1. Field of the Invention
This invention relates to chemical compounds, pharmaceutical compositions, and methods for increasing the therapeutic efficacy of drugs. Specifically, the invention relates to compounds and pharmaceutical compositions for inhibiting drug transport proteins that efflux therapeutic agents from cells, and to methods for using these compounds and compositions to increase the efficacy of the therapeutic agents that are effluxed by these drug transport proteins.
2. Background of the Invention
Eukaryotic cells possess integral membrane transport proteins which actively efflux a variety of chemical compounds from the cells (Gottesman and Pastan, 1993, Ann. Rev. Biochem. 62:385-427). In normal cells, these transport proteins serve to protect cells from cytotoxic and mutagenic compounds encountered in the diet or environment. However, these transport proteins are also very effective at removing pharmaceutical agents from target cells, thereby severely restricting the therapeutic efficacy of such agents. Consequently, compounds that inhibit these transport proteins are expected to enhance the clinical utility of drugs susceptible to such transport by enhancing drug accumulation in target cells.
Two transport proteins, P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), play important roles in the treatment of human disease. Because of this involvement in human disease, there is great interest in developing pharmaceutical agents that will effectively inhibit the function of these proteins. More recently, additional transport proteins have been identified, including cMOAT and some proteins related to MRP.
An important issue regarding P-gp and MRP relates to their substrate specificity. Pharmacological comparisons of cells overexpressing either P-gp or MRP demonstrate only a partial overlap of the resistance profiles conferred by these two proteins. For example, while MRP-transfected cells show a greater resistance to vincristine, etoposide, and doxorubicin, than to vinblastine and paclitaxel (Cole et al., 1994, Cancer Res. 54:5902-10), P-gp-transfected cells show a much greater resistance to vinblastine and paclitaxel (Smith et al., 1995, Cancer 75:2597-604). This differential pharmacology illustrates the feasibility of developing selective inhibitors of these transporters, which should provide useful methods for increasing the therapeutic efficacy of many types of pharmaceutical agents.
Another significant difference between P-gp and MRP relates to the distribution of these proteins in normal tissues. P-gp has been shown to be expressed by several types of secretory cells, such as capillary endothelial cells in the brain and testis, and at sites within the pancreas, kidney, and liver (Leveille-Webster and Arias, 1995, J. Membrane Biol. 143:89-102). In contrast, the expression of MRP mRNA occurs in virtually every type of tissue (Zaman et al., 1993, Cancer Res. 53:1747). Cells in various disease states also differentially express P-gp and MRP, indicating that selective inhibitors will be preferred as therapeutic agents.
An example of transport protein-mediated drug resistance is the phenomenon of multidrug resistance (MDR), which is often encountered in cancer chemotherapy (Gottesman and Pastan, 1993). As a result of this phenomenon, tumor cells expressing transport proteins become resistant to many structurally unrelated drugs and the proliferation of resistant tumor cells results in the failure of chemotherapeutic treatment. Tumor cells from individuals undergoing chemotherapy often demonstrate elevated P-gp expression (Goldstein et al., 1989, J. Natl. Cancer Inst. 81:116-24). Recent studies have also indicated that MRP is expressed in a high percentage of solid tumors and leukemias. However, no differences in MRP levels were detected between normal and malignant hematopoietic cells (Abbaszadegan et al., 1994, Cancer Res. 54:4676-79), and MRP levels were found to be lower in some tumors than in corresponding normal tissues (Thomas et al., 1994, Eur. J. Cancer 30A:1705-09). Therefore, it appears that different tumors display different patterns of expression of P-gp and MRP (and perhaps other transport proteins as well).
Another example of drug transporter-mediated resistance is encountered in the effort to deliver drugs to the central nervous system, testes, and eye. In the brain, the blood-brain barrier exists to exclude toxic agents from the brain, and largely derives from the high level of expression of P-gp by endothelial cells in the capillaries of the brain (Schinkel et al., 1996, J. Clin. Invest. 97:2517-24). P-gp is also highly expressed in the capillary endothelial cells of the eye (Holash and Stewart, 1993, Brain Res. 629:218-24) and testes (Holash et al., 1993, Proc. Natl. Acad. Sci. USA. 90:11069-73), restricting the uptake of many compounds by these tissues. While these systems are useful in protecting normal tissues, they also impair the delivery of therapeutic agents to these sites when such delivery may be desired. For example, the expression of P-gp in brain capillary cells impairs effective treatment of brain tumors or neurological diseases using drugs that are transported by P-gp. P-gp is also highly expressed in the liver, adrenal gland, and kidney (Lum and Gosland, 1995, Hematol. Oncol. Clin. North Amer. 9:319-36), other tissues in which drug delivery is restricted. It is envisioned that inhibition of P-gp, or other transport proteins, will facilitate drug delivery to these sites and so enhance the effectiveness of chemotherapy. It is also envisioned that drug transport protein antagonists will be useful in suppressing the secretion of endogenous compounds, including steroid hormones and cholesterol, providing therapeutic benefit under conditions in which excessive circulating levels of these compounds promote disease states.
Another example of drug transporter-mediated resistance is encountered in the effort to orally deliver therapeutic agents. The high expression of P-gp at the brush-border membrane of the small intestine reduces the bioavailability of orally administered drugs subject to transport (Sparreboom et al., 1997, Proc. Natl. Acad. Sci. U.S.A. 94:2031-35). It is envisioned that inhibition of P-gp, or other transport proteins, will facilitate drug absorption, thereby enhancing the effectiveness of chemotherapy.
Yet another example of drug transporter-mediated resistance is encountered in the effort to deliver therapeutic agents to certain leukocytes. P-gp is highly expressed by certain subtypes of lymphocytes, natural killer cells, and bone marrow stem cells (Gupta and Gollapudi, 1993, J. Clin. Immunol. 13:289-301). This reduces the therapeutic efficacy of drugs targeting these cells, including anti-HIV compounds for the treatment of AIDS (Yusa et al., 1990, Biochem. Biophys. Res. Com. 169:986-90). Furthermore, the release of inflammatory cytokines and other immunomodulators appears to involve drug transporters (Salmon and Dalton, 1996, J. Rheumatol. Suppl. 44:97-101). It is envisioned that inhibition of P-gp, or other transport proteins, will facilitate drug accumulation in these cells and so enhance the effectiveness of chemotherapy.
Organisms other than mammals also possess transport proteins similar to P-gp that have been shown to confer resistance to chemotherapeutic agents (Ullman, 1995, J. Bioenergetics Biomembranes 27:77-84). While the pharmacology of these transport proteins is not identical to that of P-gp, certain modulators are able to inhibit drug transport by both P-gp and for example, protozoan transport proteins (Frappier et al., 1996, Antimicrob. Agents Chemother. 40:1476-81). It is envisioned that certain MDR modulators will facilitate drug accumulation in non-mammalian cells and so enhance the effectiveness of anti-infection chemotherapy.
Since drug transport proteins are involved in determining the success of chemotherapy in a variety of disease states, there is a need for effective modulators of drug transport proteins. While a number of compounds have been shown to reverse transporter-mediated MDR in cell culture, the clinical success of these modulators has been unimpressive, predominantly due to their intrinsic toxicity and undesired effects on the pharmacokinetics of accompanying drugs. However, the failure of these modulators can also be attributed to their lack of selectivity for different drug transport proteins. For example, inhibition of MRP by MDR modulators is likely to increase the uptake of cytotoxic anticancer drugs by many normal tissues, thereby resulting in greater toxicity in the individual. Successful chemotherapy will consequently require a panel of transporter antagonists with differential selectivity for P-gp and MRP that will allow selection of the appropriate sensitizing agent. Thus, there remains a need in the art to develop drug transport protein modulators that are selective for P-gp and MRP. The development of such modulators, and methods for their use, would have wide application in the medical art.
The present invention provides chemical compounds, pharmaceutical compositions, and methods for increasing the therapeutic efficacy of drugs. Specifically, the invention provides compounds and pharmaceutical compositions for inhibiting drug transport proteins that efflux therapeutic agents from cells, and to methods for using these compounds and compositions to increase the efficacy of the therapeutic agents that are effluxed by these drug transport proteins.
The present invention provides chemical compounds of the formula: 
wherein
n is an integer from 1 to 12, preferably n is 1;
R1 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferably pyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, alkanoyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R2 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferably pyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, alkanoyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R3 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferably pyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, alkanoyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6); and
R8 is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), alkoxy (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6); or pharmaceutically acceptable salts thereof.
The present invention also provides chemical compounds of the formula: 
or a pharmaceutically acceptable salt thereof wherein,
R1 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferably pyridine, heteroarylalkyl heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, alkanoyl, arylalkanoyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R2 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6); or
R2 is: 
wherein R4 represents H, alkyl (C1-C6) halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, xe2x80x94NH2, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, heterocycloalkyl, preferably pyrrolyl, morpholinyl, thiomorpholinyl, piperidyl, or piperazyl, heterocycloalkylalkyl, aryl, preferably phenyl, or arylalkyl, preferably benzyl, heteroaryl, or heteroarylalkyl;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R3 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R7 is H, alkyl (C1-C6), alkoxy, alkoxycarbonyl, preferably tertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, or arylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each is optionally substituted with up to three groups that are independently alkyl, alkoxy, xe2x80x94NO2, xe2x80x94OH, halogen, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OCF3; and
R8 is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), alkoxy (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl xe2x80x94NO2 or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6).
The present invention provides pharmaceutical compositions comprising a compound of the formula: 
or a pharmaceutically acceptable salt thereof; with at least one pharmaceutically acceptable carrier or excipient, wherein
n is an integer from 1 to 12, preferably n is 1;
R1 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferably pyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH alkoxy, hydroxyalkyl, alkanoyl, xe2x80x94COOH carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R2 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferably pyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, alkanoyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R3 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, preferably phenyl, arylalkyl, preferably benzyl, heteroaryl, preferably pyridine, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, alkanoyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6); and
R8 is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), alkoxy (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6).
The present invention also provides pharmaceutical compositions comprising a compound of the formula: 
or a pharmaceutically acceptable salt thereof; with at least one pharmaceutically acceptable carrier, or excipient wherein,
R1 is, H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, alkanoyl, arylalkanoyl, xe2x80x94COOH; carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R2 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6); or
R2 is: 
wherein R4 represents H, alkyl (C1-C6), halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, xe2x80x94NH2, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, heterocycloalkyl, preferably pyrrolyl, morpholinyl, thiomorpholinyl, piperidyl, or piperazyl, heterocycloalkylalkyl, aryl, preferably phenyl, or arylalkyl, preferably benzyl, heteroaryl, or heteroarylalkyl;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R3 is H, alkyl (C1-C15), cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, halogen, haloalkyl, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94COOH, carboxamide, mono or dialkylaminocarboxamide, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CO2R8, xe2x80x94OC(O)R8, carbamoyl, mono or dialkylcarbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarboxamide, or mono or dialkylthiocarboxamide;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6);
R7 is H, alkyl (C1-C6), alkoxy, alkoxycarbonyl, preferably tertiary-butoxycarbonyl (BOC), arylalkyl, preferably benzyl, or arylalkoxycarbonyl, preferably carbobenzyloxy (Cbz), wherein each is optionally substituted with up to three groups that are independently alkyl, alkoxy, xe2x80x94NO2, xe2x80x94OH, halogen, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OCF3; and
R8 is H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;
wherein each of the above is optionally substituted with up to 5 groups that are independently alkyl (C1-C6), alkoxy (C1-C6), halogen, haloalkyl, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OH, alkoxy, hydroxyalkyl, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94S-alkyl, xe2x80x94NO2, or xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently H or alkyl (C1-C6).
The present invention provides methods for inhibiting drug transport from target cells or tissues in an animal undergoing chemotherapy, comprising administering to the animal a pharmaceutical composition of the present invention in an amount effective to inhibit drug transport from the target cells or tissues of the animal. The present invention also provides methods for preventing drug resistance in an animal undergoing chemotherapy, comprising administering to the animal a pharmaceutical composition of the present invention in an amount effective to attenuate drug resistance. The methods of the present invention may be useful for treating MDRxe2x80x94by reversing MDR or chemosensitizing multidrug resistant cells to anti-cancer agentsxe2x80x94or preventing MDR.
The present invention further provides methods for enhancing the therapeutic efficacy of an antiproliferative drug in target cells or tissues of an animal, comprising administering to the animal a pharmaceutical composition of the present invention in an amount effective to enhance delivery of the antiproliferative drug to the target cells or tissues of the animal.
The present invention still further provides methods for enhancing the therapeutic efficacy of an anti-infective agent in an animal, comprising administering to the animal a pharmaceutical composition of the present invention in an amount effective to inhibit drug transport from an infectious agent in the animal.
The present invention still further provides methods for enhancing the delivery of a therapeutic agent to target cells or tissues of an animal, comprising administering to the animal a pharmaceutical composition of the present invention in an amount effective to enhance delivery of the therapeutic agent to the target cells or tissues of the animal. The methods of the present invention may be useful for enhancing the delivery to target cells or tissues such as the brain, testes, eye, or leukocytes.
The present invention still further provides methods for enhancing the absorption of an orally-delivered therapeutic agent in an animal, comprising administering to the animal a pharmaceutical composition of the present invention in an amount effective to enhance drug transport across the gastrointestinal tract.
The present invention provides a panel of novel drug transport inhibitors. The chemical compounds, pharmaceutical compositions, and methods of the present invention provide important new therapeutic tools for treating or preventing a variety of diseases or conditions related to drug transport.
Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.